The invention relates to methods and compositions for the treatment of severe chronic bronchitis or bronchiectasis by endobronchial delivery of aminoglycoside antibiotic compounds, such as tobramycin. In particular, the invention concerns formulations including aminoglycoside powders or concentrated solutions having pH between 5.5 and 7.0. The formulations permit delivery of aminoglycoside antibiotic compounds to the lung endobronchial space of airways in dry powder form or as an aerosol having mass medium average diameter predominantly between 1 to 5xcexc. The formulated and delivered efficacious amount of aminoglycoside antibiotic compound, such as tobramycin, is sufficient for treatment and prophylaxis of acute and chronic endobronchial infections, particularly those caused by the bacterium Pseudomonas aeruginosa. In other aspects, the invention relates to the endobronchial delivery of effective amounts of an aminoglycoside antibiotic, such as tobramycin, to patients with bronchiectasis with P. aeruginosa to cause substantially complete eradication of the organism. The novel formulations have small volume yet deliver effective doses of aminoglycoside antibiotic compounds to the site of the infection.
Bronchiectasis is defined as irreversible abnormal dilatation of the airways. Bronchiectasis can be caused by either acquired or congenital mechanisms that disrupt the normal processes of airway clearance and/or host defense. These causes may include ciliary motility disorders and cystic fibrosis (CF), or processes that cause persistent damage, such as a bacterial or viral pneumonia. Defects in host defense such as agammaglobulinemia, or mechanical processes such as foreign bodies that cause post-obstructive infection can also result in bronchiectasis (Barker, A. F. et al., xe2x80x9cBronchiectasis: update of an orphan disease,xe2x80x9d Am Rev Respir Dis; 137(4):969-78(1988)). Morbidity from bronchiectasis is caused by persistent airway infection. Treatment of infection may reduce morbidity. The microbiology of lung infections in CF has been well characterized, with Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa colonizing in an age-related sequence. P. aeruginosa infects 60% of all patients with CF (Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Patient Registry, Annual Data Report 1992, (1993)). However, the microbiology of bronchiectasis in patients without CF has not been well-characterized. One retrospective study of bronchiectasis found the most frequently isolated organisms to be P. aeruginosa (30.9% of patients), Haemophilus influenzae (30.1%), mycobacteria (22.8%), Mycobacterium avium-intracelluare (17.1%), other Gram-negative bacilli (13%), and Streptococcus pneumoniae (10.6%) (Nicotra, M. B. et al., xe2x80x9cClinical, pathophysiologic, and microbiologic characterization of bronchiectasis in an aging cohort,xe2x80x9d Chest 108(4):955-61 (1995)).
Clinically, bronchiectasis is characterized by chronic airway infection, associated with intermittent exacerbations. Infection may manifest by expectoration of purulent sputum, fever, malaise, and weight loss. The density of P. aeruginosa in sputum in patients with exacerbations of bronchiectasis has been estimated at 107 cfu/mL (Currie D. C. et al., xe2x80x9cSimple method of monitoring colonizing microbial load in chronic bronchial sepsis: pilot comparison of reduction in colonizing microbial load with antibiotics given intermittently and continuously,xe2x80x9d J Clin Pathol 40:830-836 (1987)). Exacerbations may be treated with oral or parenteral antibiotics, but the options for treatment of P. aeruginosa are limited. One common regimen, a 14-21 day course of parenteral aminoglycoside in combination with a third-generation cephalosporin, is widely used but has several disadvantages. The penetration of parenterally-administered aminoglycosides into bronchial secretions is poor and thus hill doses must be given in order to achieve high sputum concentrations (Pennington J. E., xe2x80x9cPenetration of antibiotics into respiratory secretions,xe2x80x9d Rev Infect Dis 3(1):67-73 (1981)). High doses and multiple courses of therapy lead to high serum concentrations and increase the risk of serious adverse effects, such as ototoxicity and nephrotoxicity. Treatment of patients with bronchiectasis with P. aeruginosa seldom, if ever, eradicates the organismsxe2x80x94most of the treatment benefit from either oral or IV antibiotics just suppresses growth, with regrowth occurring after discontinuation of antibiotic therapy. Therefore, any method that can eradicate infection for any period of time would be useful, novel and an advance in the art.
Tobramycin is commonly prescribed for the treatment of serious infections with P. aeruginosa. It is an aminoglycoside antibiotic produced by the actinomycete, Streptomyces tenebrarius. Low concentrations of tobramycin ( less than 4 xcexcg/mL) are effective in inhibiting the growth of many Gram-negative bacteria and under certain conditions may be bactericidal (Neu. H. C., xe2x80x9cTobramycin: an overview,xe2x80x9d J Infect Dis 134, Suppl: S3-19 (1976)). Tobramycin is poorly absorbed across mucosal surfaces, necessitating parenteral administration. Tobramycin activity is inhibited by purulent sputum: high concentrations of divalent cations, acidic conditions, increased ionic strength and macromolecules that bind the drug all inhibit tobramycin in this environment. It is estimated that 5-10xc3x97 higher concentrations of tobramycin are required in the sputum to overcome these inhibitory effects (Ledy J. et al., xe2x80x9cBioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,xe2x80x9d J Infect Dis 148(6):1069-76 (1983)).
Delivery of the poorly absorbed antibiotic tobramycin to the airway by the aerosol route of cystic fibrosis (CF) patients has been documented using the aerosol route. Much of this work has been done toward treatment of chronic lung infections with P. aeruginosa in cystic fibrosis (CF) patients. A multicenter, double blind, placebo-controlled, crossover trial of 600 mg tid of aerosolized tobramycin for endobronchial infections due to P. aeruginosa in 71 CF patients demonstrated a significant reduction in sputum density of this pathogen as well as improved spirometry in the treatment group. Emergence of P. aeruginosa strains highly resistant to tobramycin (defined as MIC  greater than 128 xcexcg/mL) was comparable in the placebo and treatment groups. The presence in the sputum of Gram-negative organisms other than P. aeruginosa intrinsically resistant to tobramycin occurred with equal frequency during administration of tobramycin or placebo (Ramsey B. et al., xe2x80x9cResponse to Letter to the Editor: Aerosolized tobramycin in patients with cystic fibrosis,xe2x80x9d N Engl J Med 329:1660 (1993)).
Although this regimen was found to be both safe and efficacious, it is costly and inconvenient. A survey of the MICs for P. aeruginosa isolates from initial sputum cultures for patients at the Children""s Hospital CF Center, Seattle, Wash., in 1993 found that 90% of isolates had MICs  less than 16 xcexcg/mL and 98% of all isolates had MICs xe2x89xa6128 xcexcg/mL. This survey suggested that achieving a sputum tobramycin concentration of 128 xcexcg/mL should treat the endobronchial infection in CF patients (Levy J. et al., xe2x80x9cBioactivity of gentamicin in purulent sputum from patients with cystic fibrosis or bronchiectasis: comparison with activity in serum,xe2x80x9d J Infect Dis 148(6):1069-76 (1983)).
A randomized, cross-over study compared the ability of several nebulizers to deliver tobramycin by measuring peak sputum tobramycin concentrations in samples collected ten minutes after completion of the aerosol dose. This study used a new formulation. TOBI(copyright), PathoGenesis Corporation, Seattle, Wash., containing 60 mg/mL, tobramycin in 5 mL one quarter (xc2xc) normal saline. The Pari(copyright) LC jet nebulizer, Pari Respiratory Equipment, Inc., Richmond, Va., delivered a mean peak sputum tobramycin concentration of 678.8 xcexcg/g (s.d. 661.0 xcexcg/g), and a median peak sputum concentration of 433.0 xcexcg/g. Only 13% of patients had sputum levels xe2x89xa6128 xcexcg/g: 87% of patients achieved sputum levels of xe2x89xa7128 xcexcg/g (Eisenberg, J. et al., xe2x80x9cA Comparison of Peak Sputum Tobramycin Concentration in Patients With Cystic Fibrosis Using Jet and Ultrasonic Nebulizer Systems. Aerosolized Tobramycin Study Group,xe2x80x9d Chest 111 (4):955-962 (1997)). This nebulizer completes nebulization in a short time (ten minutes) and produces particles of an ideal mass median aerodynamic diameter (3.3 xcexcm).
Recently, the Pari(copyright) LC jet nebulizer has been slightly modified with the addition of one-way flow valves, and renamed the Pari(copyright) LC Plus. In vitro experiments using a test lung suggest that the Pari(copyright) LC Plus delivers up to 20% more drug than the Pari(copyright) LC jet nebulizer. The particle size is identical. The one-way valves also decrease the potential for accidental spillage and allow for the use of an expiratory filter. For these reasons, the Pari(copyright) LC Plus jet nebulizer was selected for use in two large Phase 3 trials of TOBI for chronic P. aeruginosa infection in CF patients. Preliminary data from these Phase 3 studies show that mean peak sputum tobramycin concentrations achieved using the Pari LC Plus jet nebulizer are significantly higher than those using the Pari(copyright) LC jet nebulizer as described in Eisenberg et al. (1997), supra.
Two placebo-controlled, multicenter, randomized, double-blind clinical trials of intermittent administration of inhaled tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa infection were reported in Ramsey, B. W. et al., xe2x80x9cIntermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.xe2x80x9d N. Engl. J. Med. 340(1):23-30 (1999). In these studies, five hundred twenty subjects were randomized to receive either 300 mg inhaled tobramycin or placebo twice daily for 28 days followed by 28 days off study drug. Subjects continued on treatment or placebo for three xe2x80x9con-offxe2x80x9d cycles for a total of 24 weeks. Efficacy variables included sputum P. aeruginosa density. Tobramycin-treated patients had an average 0.8 log10 decrease in P. aeruginosa density from Week 0 to Week 20, compared with a 0.3 log10 increase in placebo-treated patients (P less than 0.001). Tobramycin-treated patients had an average 1.9 log10 decrease in P. aeruginosa density from Week 0 to Week 4, compared with no change in placebo-treated patients (P less than 0.001).
One aspect of the current invention is a method for treatment of severe chronic bronchitis or bronchiectasis caused by Pseudomonas aureginosa or other pseudomonads by administering to the patient requiring such treatment a formulation comprising about one to ten thousand times higher concentration of an effective aminoglycoside antibiotic, such as tobramycin, than its minimal inhibitory concentration (MIC).
In another aspect, the current invention provides methods for treatment of severe chronic bronchitis or bronchiectasis caused by Pseudomonas aureginosa or other pseudomonads by administering to a patient requiring such treatment effective amounts of a suitable aminoglycoside antibiotic by an endobronchial route of administration. In a representative embodiment of this aspect of the invention, the antibiotic may be endobronchially administered twice daily, for at least one day, more preferably for at least five days, and most preferably for at least fourteen days, in a formulation comprising about 8 to about 80 mg/ml of a suitable aminoglycoside antibiotic, such as tobramycin, dissolved in a full or quarter normal saline having a pH between 5.5 and 7.0. In other representative embodiments, the antibiotic may be administered in powdered form by a dry powder inhaler or metered dose inhaler, or solution form by a jet or ultrasonic nebulizer in 5 ml concentrated form in an aerosol producing a particle size having the mass medium average diameter predominately between 1 and 5xcexc.
Still other aspects of the current invention provide methods for treatment of severe chronic bronchitis or bronchiectasis caused by Pseudomonas aureginosa by administering to the patient requiring such treatment a formulation comprising about 40 to about 400 mg, more preferably about 300 mg, of a suitable aminoglycoside antibiotic, such as tobramycin, dissolved in 5 ml of a quarter normal saline adjusted to a pH about 5.5 to about 7.0.
Still another aspect of the current invention is a formulation for treatment of severe chronic bronchitis or bronchiectasis comprising a concentration from about 8 to about 80 mg/ml of tobramycin dissolved in about 5 ml of a full or quarter normal strength saline wherein said tobramycin concentration is one to ten thousand times higher than the MIC of tobramycin.
Still another aspect of the current invention is a method for treatment of severe chronic bronchitis caused by the bacteria Streptococus pneumoniae, Haemophilus influenzae, Staphylococus aureus, and Moraxella catarrhalis and the atypical pneumonias Legionella pneumonia, Chlamydia pneumoniae, and Mycoplasma pneumoniae including Pseudomonas aeruginosa by administering to a patient requiring such treatment a formulation of an antibiotic by aerosol delivery, wherein the formulation comprises about 8 to about 80 mg/ml of tobramycin in about 1 to about 5 ml of saline diluted into a quarter normal saline strength wherein said formulation has a pH between 5.5 and 7.0 and is delivered by a jet nebulizer in 5 ml concentrated form in an aerosol producing a particle size hating the mass medium average diameter predominantly between 1 and 5xcexc.
The foregoing aspects of the invention have been confirmed in a placebo-controlled, randomized study conducted to evaluate the microbiological efficacy and safety of inhaled tobramycin for treatment of patients with bronchiectasis and P. aeruginosa. The results obtained in bronchiectasis were highly significant, with the antimicrobial efficacy greater than 10,000 fold greater than in cystic fibrosis patients. In the study, 20% of the bronchiectasis patients had complete eradication, a finding rare with either oral or intravenous therapy. In fact, in spite of 20 years of use of intravenous tobramycin, usually in combination with another antibiotic, results such as these have not been reported. Thus, the results obtained teach the following:
1. Aerosolized aminoglycoside antibiotics can be extremely effective in treatment of bronchiectasis;
2. The aerosol route improves the efficacy of an agent even if given intravenously; and
3. The duration of therapy does not need to be long term; efficacy was seen in two weeks.
Since bronchiectasis is the most severe form of chronic bronchitis, these results teach that short course aerosol antibiotics are effective in treating the disorder.